Integrated modelling of the clinical pharmacokinetics of SDZ HTF 919, a novel selective 5-HT4 receptor agonist, following oral and intravenous administration. (1/104)

AIMS: The purpose of the present study was to assess the pharmacokinetics of the novel selective 5-HT4 receptor agonist SDZ HTF 919 (HTF) including food effect, absolute bioavailability, interoccasion and intersubject variabilities. METHODS: In the randomized, open-label, three treatment, four period crossover study, HTF was administered to 12 young healthy male subjects as a 12 mg tablet (twice under fasted and once under fed conditions) and a 3 mg intravenous (i.v.) infusion over 40 min (fasted). Pharmacokinetic parameters were obtained by noncompartmental methods. A more comprehensive pharmacokinetic characterization was achieved by integrated modelling of oral (p.o.) and i.v. data. To describe the absorption phase a Weibull function and a classical first order input function were compared. RESULTS: Noncompartmental pharmacokinetic analysis revealed a rapid absorption (tmax 1.3 h, fasted), an absolute bioavailability of 11+/-3%, a biphasic disposition phase with a terminal half-life of 11+/-5 h, a clearance of 77+/-15 l h-1, and a volume of distribution at steady state of 368+/-223 l. The coefficients of interoccasion and interindividual variability in Cmax and AUC ranged between 17 and 28%. Food intake caused a delay (tmax 2.0 h) and decrease in absorption with consequently lower systemic exposure ( approximately 5% absolute bioavailability). Integrated p.o./i.v. pharmacokinetic modelling with a Weibull input function allowed accurate description of individual profiles. Modelling of the data from the p.o. dosing improved the description of the terminal phase by inclusion of the i. v. data and additionally provided quantitative characterization of the absorption phase. CONCLUSIONS: The pharmacokinetics of HTF could be well described by an integrated modelling approach for both p.o. and i.v. data. The derived model will provide guidance in the design of future studies.  (+info)

Non-absorbable antibiotics for managing intestinal gas production and gas-related symptoms. (2/104)

BACKGROUND: Simethicone, activated charcoal and antimicrobial drugs have been used to treat gas-related symptoms with conflicting results. AIM: To study the relationship between gaseous symptoms and colonic gas production and to test the efficacy of rifaximin, a new non-absorbable antimicrobial agent, on these symptoms. METHODS: Intestinal gas production was measured by hydrogen (H2) and methane (CH4) breath testing after lactulose in 21 healthy volunteers and 34 functional patients. Only the 34 functional patients took part in a double-blind, double-dummy controlled trial, receiving, at random, rifaximin (400 mg b.d per 7 days), or activated charcoal (400 mg b.d per 7 days). The following parameters were evaluated at the start of the study and 1 and 10 days after therapy: bloating, abdominal pain, number of flatus episodes, abdominal girth, and cumulative breath H2 excretion. RESULTS: Hydrogen excretion was greater in functional patients than in healthy volunteers. Rifaximin, but not activated charcoal, led to a significant reduction in H2 excretion and overall severity of symptoms. In particular, in patients treated with rifaximin, a significant reduction in the mean number of flatus episodes and of mean abdominal girth was evident. CONCLUSIONS: In patients with gas-related symptoms the colonic production of H2 is increased. Rifaximin significantly reduces this production and the excessive number of flatus episodes.  (+info)

Impaired transit and tolerance of intestinal gas in the irritable bowel syndrome. (3/104)

BACKGROUND: Patients with irritable bowel syndrome (IBS) frequently complain of excessive gas but their fasting volume of intestinal gas is apparently normal. We hypothesised that the pathophysiological mechanism involved may be impairment of intestinal gas transit. AIM: To investigate intestinal gas transit and tolerance in IBS patients compared with healthy subjects. METHODS: A gas mixture (N(2), O(2), and CO(2) in venous proportions) was infused into the jejunum of 20 patients with IBS and 20 healthy controls at 12 ml/min for four hours. Gas evacuation, initially flatus from the anus (two hours) and then intrarectally (two hours), was continuously recorded. Symptom perception (0-6 scale) and abdominal distension were measured at 10 minute intervals. RESULTS: After two hours of external gas (flatus) collection, 18 of 20 IBS patients had developed gas retention (>400 ml), increased gastrointestinal symptoms (score >3), or abdominal distension (>3 mm girth increment) compared with only four of 20 control subjects. During intrarectal gas collection, 13 of 17 patients still exhibited abnormal responses. CONCLUSION: A large proportion of patients with IBS can be shown to have impaired transit and tolerance of intestinal gas loads. This anomaly may represent a possible mechanism of IBS symptoms, specifically pain and bloating.  (+info)

Prebiotic digestion and fermentation. (4/104)

Prebiotics, as currently conceived of, are all carbohydrates of relatively short chain length. To be effective they must reach the cecum. Present evidence concerning the 2 most studied prebiotics, fructooligosaccharides and inulin, is consistent with their resisting digestion by gastric acid and pancreatic enzymes in vivo. However, the wide variety of new candidate prebiotics becoming available for human use requires that a manageable set of in vitro tests be agreed on so that their nondigestibility and fermentability can be established without recourse to human studies in every case. In the large intestine, prebiotics, in addition to their selective effects on bifidobacteria and lactobacilli, influence many aspects of bowel function through fermentation. Short-chain fatty acids are a major product of prebiotic breakdown, but as yet, no characteristic pattern of fermentation acids has been identified. Through stimulation of bacterial growth and fermentation, prebiotics affect bowel habit and are mildly laxative. Perhaps more importantly, some are a potent source of hydrogen in the gut. Mild flatulence is frequently observed by subjects being fed prebiotics; in a significant number of subjects it is severe enough to be unacceptable and to discourage consumption. Prebiotics are like other carbohydrates that reach the cecum, such as nonstarch polysaccharides, sugar alcohols, and resistant starch, in being substrates for fermentation. They are, however, distinctive in their selective effect on the microflora and their propensity to produce flatulence.  (+info)

Helicobacter pylori infection as a risk factor for gastrointestinal symptoms in patients using aspirin to prevent ischaemic heart disease. (5/104)

BACKGROUND: Aspirin use in the secondary prevention of ischaemic heart disease may provoke gastrointestinal discomfort. OBJECTIVE: To register gastrointestinal symptoms and complications in patients with cardiovascular disease using aspirin and to relate these symptoms to infection with H. pylori. METHODS: Blood samples were obtained from 398 consecutive patients in the Coronary-Care Unit, University Hospital Nijmegen and analysed for serum antibody levels to H. pylori infection. Questionnaires were sent 2 weeks after discharge to assess gastrointestinal symptoms. RESULTS: Questionnaires were returned by 314 patients (79%). A total of 183 out of 314 patients (46%) reported gastrointestinal symptoms. Of 238 patients using 80-100 mg aspirin daily, 145 (61%) recorded gastrointestinal symptoms. Besides aspirin, the use of calcium antagonists was correlated with gastrointestinal symptoms. Of the 128 patients using calcium antagonists, 84 (66%) reported gastrointestinal symptoms. The prevalence of gastrointestinal symptoms in H. pylori-positive and -negative patients using aspirin was 48% and 52%, respectively. CONCLUSIONS: Two weeks after discharge almost 50% of the patients with cardiovascular disease experienced gastrointestinal symptoms, especially patients using aspirin or calcium antagonists. Patients seropositive for H. pylori and using aspirin or calcium antagonists did not have more gastrointestinal discomfort compared to non-infected patients.  (+info)

Lactose intolerance among Mexican Americans. (6/104)

Thirty-three Mexican Americans between the ages of 9 and 60 were interviewed and tested for lactose intolerance. The participants of the study included 16 children and 17 persons not related by birth, including the parents of the children. Determination of lactose intolerance was based on a rise of less than 25mg/100 ml of blood glucose as measured by an Ames Dextrostix/Reflectance Meter following consumption of a lactose load. Forty-seven percent of the 17 nonrelated Mexican Americans were lactose intolerant. There was a marked relationship between low rise in blood glucose and symptoms of diarrhea, flatulence, and distention. Sixteen children from four families had an incidence of 50 per cent intolerance. The findings of intolerance in two successive generations of three families and in both sexes of the families adds support to the contention that lactose intolerance has a genetic basis, without sex predilection.  (+info)

A study of fructo oligosaccharides in the prevention of travellers' diarrhoea. (7/104)

BACKGROUND: Prebiotic carbohydrates selectively stimulate the growth of bifidobacteria and lactobacilli in the human colon. These bacteria form part of the gut's inherent defence against invading pathogens. AIM: To test the effectiveness of fructo oligosaccharides in preventing travellers' diarrhoea. METHODS: A total of 244 healthy subjects, travelling to high and medium risk destinations for travellers' diarrhoea, took part in a randomized, double-blind, placebo-controlled study. The protocol comprised a preliminary week for recording bowel habit by diary, a 2-week pre-holiday period with the diary and consumption of 10 g of fructo oligosaccharides or placebo daily, followed by a 2-week holiday with continuation of treatment and diary. A post-study questionnaire was completed by all subjects on their return to the UK. RESULTS: The consumption of fructo oligosaccharides led to a small (6%; P < 0.02) increase in stool frequency in the pre-holiday period and gave a significantly better sense of 'well-being' during the holiday, although subjects reported more flatulence. There were non-significant decreases in episodes of diarrhoea with 20% on placebo and 11% on fructo oligosaccharides recording episodes in the post-study questionnaire (P=0.08) and 46% placebo, 38% fructo oligosaccharides recording episodes in the diary (P > 0.1). No change in bowel frequency, consistency or stool size was recorded. CONCLUSION: Travel to high risk areas increases diarrhoea. Fructo oligosaccharides alone are not sufficient to prevent this, although do have some benefits for the subjects.  (+info)

Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release. (8/104)

We investigated the effect of acarbose, an alpha-glucosidase and pancreatic alpha-amylase inhibitor, on gastric emptying of solid meals of varying nutrient composition and plasma responses of gut hormones. Gastric emptying was determined with scintigraphy in healthy subjects, and all studies were performed with and without 100 mg of acarbose, in random order, at least 1 wk apart. Acarbose did not alter the emptying of a carbohydrate-free meal, but it delayed emptying of a mixed meal and a carbohydrate-free meal given 2 h after sucrose ingestion. In meal groups with carbohydrates, acarbose attenuated responses of plasma insulin and glucose-dependent insulinotropic polypeptide (GIP) while augmenting responses of CCK, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). With mixed meal + acarbose, area under the curve (AUC) of gastric emptying was positively correlated with integrated plasma response of GLP-1 (r = 0.68, P < 0.02). With the carbohydrate-free meal after sucrose and acarbose ingestion, AUC of gastric emptying was negatively correlated with integrated plasma response of GIP, implying that prior alteration of carbohydrate absorption modifies gastric emptying of a meal. The results demonstrate that acarbose delays gastric emptying of solid meals and augments release of CCK, GLP-1, and PYY mainly by retarding/inhibiting carbohydrate absorption. Augmented GLP-1 release by acarbose appears to play a major role in the inhibition of gastric emptying of a mixed meal, whereas CCK and PYY may have contributory roles.  (+info)